PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation.

Wimmer, Isabella; Tietz, Silvia; Nishihara, Hideaki; Deutsch, Urban; Sallusto, Federica; Gosselet, Fabien; Lyck, Ruth; Muller, William A; Lassmann, Hans; Engelhardt, Britta (2019). PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation. Frontiers in immunology, 10, p. 711. Frontiers Research Foundation 10.3389/fimmu.2019.00711

[img]
Preview
Text
fimmu-10-00711.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (9MB) | Preview

Breakdown of the blood-brain barrier (BBB) and increased immune cell trafficking into the central nervous system (CNS) are hallmarks of the pathogenesis of multiple sclerosis (MS). Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is expressed on cells of the vascular compartment and regulates vascular integrity and immune cell trafficking. Involvement of PECAM-1 in MS pathogenesis has been suggested by the detection of increased levels of soluble PECAM-1 (sPECAM-1) in the serum and CSF of MS patients. Here, we report profound upregulation of cell-bound PECAM-1 in initial (pre-phagocytic) white matter as well as active cortical gray matter MS lesions. Using a human in vitro BBB model we observed that PECAM-1 is not essential for the transmigration of human CD4+ T-cell subsets (Th1, Th1*, Th2, and Th17) across the BBB. Employing an additional in vitro BBB model based on primary mouse brain microvascular endothelial cells (pMBMECs) we show that the lack of endothelial PECAM-1 impairs BBB properties as shown by reduced transendothelial electrical resistance (TEER) and increases permeability for small molecular tracers. Investigating T-cell migration across the BBB under physiological flow by in vitro live cell imaging revealed that absence of PECAM-1 in pMBMECs did not influence arrest, polarization, and crawling of effector/memory CD4+ T cells on the pMBMECs. Absence of endothelial PECAM-1 also did not affect the number of T cells able to cross the pMBMEC monolayer under flow, but surprisingly favored transcellular over paracellular T-cell diapedesis. Taken together, our data demonstrate that PECAM-1 is critically involved in regulating BBB permeability and although not required for T-cell diapedesis itself, its presence or absence influences the cellular route of T-cell diapedesis across the BBB. Upregulated expression of cell-bound PECAM-1 in human MS lesions may thus reflect vascular repair mechanisms aiming to restore BBB integrity and paracellular T-cell migration across the BBB as it occurs during CNS immune surveillance.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

UniBE Contributor:

Wimmer, Isabella; Tietz, Silvia; Nishihara, Hideaki; Deutsch, Urban; Lyck, Ruth and Engelhardt, Britta

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1664-3224

Publisher:

Frontiers Research Foundation

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

12 Nov 2019 09:36

Last Modified:

24 Nov 2019 02:44

Publisher DOI:

10.3389/fimmu.2019.00711

PubMed ID:

31024547

Uncontrolled Keywords:

PECAM-1 T-cell diapedesis blood-brain barrier endothelial junctions multiple sclerosis vascular permeability

BORIS DOI:

10.7892/boris.134680

URI:

https://boris.unibe.ch/id/eprint/134680

Actions (login required)

Edit item Edit item
Provide Feedback